Swine dysentery (SD), caused by colonic infection with the spirochaete Brachyspira hyodysenteriae, remains a major problem worldwide. It affects swine mainly during the fattening period. Brachyspira hyodysenteriae is a Gram-negative, oxygen-tolerant, anaerobic spirochete that colonizes the porcine large intestine to cause swine dysentery (SD). This condition is characterized by a severe mucohemorrhagic diarrhoea that primarily affects animals during the growing-finishing period and has been reported from all major pig-rearing countries (Hidalgo, A. et al., Journal of Clinical Microbiology (2010), 48(8):2859-2865).
SD is a widely distributed disease around the world, although studies regarding epidemiology are scarce and the reported prevalence significantly varies among them. Thus, B. hyodysenteriae reported prevalence ranges from 0% to near 40%. Variations in prevalence can be due to the use of different diagnostic methods or to differences among countries in housing, management, feeding regimes, etc. Moreover, whereas in many countries the prevalence may be concealed by the use of antimicrobials as feed additives, in others the ban of antibiotics as growth promoters may have resulted in an increase in SD prevalence (Alvarez-Ordóñiez, A. et al., International Journal of Environmental Research and Public Health (2013), 10:1927-1947).
Carrier pigs play a main role in the epidemiology of swine dysentery and are considered the major source of transmission between herds. B. hyodysenteriae survives in the environment for long periods, especially in liquid faeces contained in pits and lagoons, where it may remain infective for up to 60 days. For instance, it can survive during several months in pig faeces at low temperatures. This spirochete also can naturally colonize mice, rheas, chickens, and mallards, and together with mechanical vectors or fomites, this increases the ways in which B. hyodysenteriae may be spread within and between herds (Hidalgo, A. et al., Journal of Clinical Microbiology (2010), 48(8):2859-2865).
The disease causes important direct financial losses, especially in intensive pig farms, derived from a decrease in food conversion efficiency, mortality, lengthening of the fattening period and also indirect losses, like an increase in veterinary expenses, medication, etc. The eradication of the disease through medication is quite difficult, since many clinically recovered animals keep shedding the organism for a long time while acting as carriers.
Treatment of SD involves the use of antibiotics. Pleuromutilins (tiamulin and valnemulin) have been used for this purpose in the European Union (EU). Tiamulin and valnemulin are semi-synthetic derivatives of the naturally occurring diterpene antibiotic pleuromutilin which show outstanding activity against anaerobic bacteria and are used exclusively in animals, largely in swine. Also macrolides (tylosin and, more recently, tylvalosin) and the closely related lincomycin (lincosamide) have been commonly included in SD therapeutic strategies. However, the emergence of B. hyodysenteriae strains with reduced susceptibility to one or more of these antibiotics and the presence of genetically diverse multiresistant isolates has been confirmed in several countries. This fact complicates treatment and control of SD and should alert veterinary surgeons and pig farmers for the need of a strategic approach to select antibiotics, which must only be used on strict indications following proper field and laboratory diagnosis in order to guarantee their long-term efficiency for SD treatment (Alvarez-Ordóñiez, A. et al., International Journal of Environmental Research and Public Health (2013), 10:1927-1947).
The high costs of medication, together with the fact that on many occasions it is impossible to eradicate the infection completely, and the increasing worries about the presence of drug residues in both meat products and the environment, justifies the development of efficient immunoprophylactic methods to control SD (Diego, R. et al., Vaccine (1995), 13(7):663-667).
Large efforts have been made in order to develop vaccines to control SD since Joens and co-authors (Joens, L. A., et al., American Journal of Veterinary Research (1979), 40:1352-1354) reported that pigs which have recovered from acute SD are protected from disease when subsequently re-exposed to B. hyodysenteriae, indicating that the infection can induce a protective immune response (Alvarez-Ordóñiez, A. et al., International Journal of Environmental Research and Public Health (2013), 10:1927-1947). However, attempts to develop vaccines to control SD have met with limited success. Hudson (Hudson, M. J. et al., British Veterinary Journal (1974), 130:37-40; Hudson, M. J. et al., Research in Veterinary Science (1976), 21:366-367) developed an attenuated live vaccine which was unable to protect against a subsequent challenge. Glock (Glock, R. D. et al., Proceedings of the 6th International Pig Veterinary Society Congress (1980), Copenhagen, Denmark, p. 521) reported some degree of protection upon challenge after six intravenous injections, at six-day intervals, of an inactivated vaccine. Attenuated or genetically modified live avirulent vaccines may show reduced colonization and cause less immune stimulation (Alvarez-Ordóñiez, A. et al., International Journal of Environmental Research and Public Health (2013), 10:1927-1947).
An alternative approach is to generate subunit vaccines that might be delivered by the expression of recombinant B. hyodysenteriae proteins on a bacterial delivery vector. Efforts have been made to identify B. hyodysenteriae proteins for use in subunit vaccines, but vaccination with a recombinant 38 kDa flagellar protein failed to prevent colonization in experimentally infected pigs (Gabe et al., Infection and Immunity (1995), 63:142-148). On the other hand, vaccination with a recombinant 29.7 kDa outer membrane lipoprotein (Bhlp29.7) resulted in partial protection, with fewer animals developing disease than occurred in the control groups. The authors of this study concluded that vaccination also tended to delay the onset of faecal shedding of spirochaetes, but did not necessarily stop it from occurring (La, T. et al., Veterinary Microbiology (2004), 102:97-109). On a study conducted by Holden et al., the efficacy of vaccination with smpB (an outer membrane protein of B. hyodysenteriae) was evaluated. However, the response induced after protein vaccination offered only moderate protection against the disease (Holden, J. et al., Veterinary Microbiology (2008), 128:354-363). In most occasions recombinant vaccines tested have failed to provide enough protection in pigs (Alvarez-Ordóñiez, A. et al., International Journal of Environmental Research and Public Health (2013), 10:1927-1947).
Vaccines consisting of whole cell bacterins induce serum antibody responses to Brachyspira hyodysenteriae, yet generally fail to protect pigs from disease. The use of B. hyodysenteriae bacterins prepared from whole cell lysates may even exacerbate disease upon infection (Waters, W. R. et al., Vaccine (2000), 18:711-719). Moreover, bacterin vaccines tend to be lipopolysaccharide serogroup-specific, which then requires the use of autogenous bacterins. Furthermore, B. hyodysenteriae bacterins are relatively difficult and costly to produce on large scale because of the fastidious growth requirements of the anaerobic spirochaete (La, T. et al., Veterinary Microbiology (2004), 102:97-109). In some countries, bacterin vaccines for SD are available commercially, and provide a degree of protection. However, as stated above, they tend to be lipooligosaccharide (LOS) serogroup specific, which then requires the use of autogenous or multivalent preparations (Hampson, D. J. et al., Diseases of Swine (2006), 10th Edition, Blackwell Publishing Professional, Ames, Iowa, U.S.A., pp. 687-688). Other references to SD vaccines in the art can be found in the following patent literature:
U.S. Pat. No. 4,748,019: The authors found that an effective regime of vaccination comprises administering parenterally to pigs a priming dose of killed virulent or pathogenic T. hyodysenteriae effective to stimulate the immune response of the pig (strain “P18A”, NCTC 11615) to a subsequent dose of a live avirulent or non-pathogenic strain of T. hyodysenteriae (strain “VSI”, NCTC 11628) and at about the same time or thereafter administering this live strain orally.
U.S. Pat. No. 5,750,118: The invention relates to a vaccine against SD comprising an effective quantity of inactivated and adjuvant-containing T. hyodysenteriae antigen (virulent or attenuated strain) for intradermal administration. The vaccine antigen is prepared from the strain No. 27164 ATCC, which is inactivated.
U.S. Pat. No. 5,281,416: The invention relates to a method of vaccination of a pig against SD characterized by parenteral, preferably intramuscular administration to the pig of a live strain or of an oxygen-treated non-viable strain of T. hyodysenteriae. Representative strains which may be used are reference virulent strains ATCC 31287, ATCC 31212 and the reference avirulent strain ATCC 27164.
EP 3013363: The application relates to compositions and vaccines comprising combinations of different genetically diverse strains of B. hyodysenteriae. Further identified in the application are strains CNCM I-4720, CNCM I-4721 and CNCM I-4722.
However, the efficacy of these vaccines was found to be variable. In some cases, when different strains are used as ingredients of a vaccine, it can be difficult to put into practice with regard to regulatory constraints. For example, according to European regulation, each active substance in a veterinary medicine composition must be both perfectly identified and quantified in the active substance. Therefore, if a composition comprises several strains, it can be necessary to develop tests that are able to both identify and quantify each strain individually. Such tests can be very difficult to develop from a technical point of view. Autogenous preparations (also known as “autovaccines”, which may be defined as vaccines prepared from cultures of organisms isolated from the diseased animal's own tissues or secretions) have been used to further improve some of these vaccines. This approach, albeit efficient, is highly cost and time expensive and confers protection only for a single strain of B. hyodysenteriae. Moreover, the vaccination occurs sometime after the strain causing the disease has been identified, which can take several weeks (for instance, under standard procedures, the isolation process from the samples from the farm, initial culture and autovaccine production may take at least 6 weeks). This delay in time often causes the propagation of the bacteria in other animals from the herd, or in extreme circumstances, even to other pig farms. It also provokes serious economic losses and it is itself an expensive procedure to be applied on routine basis. SD thus remains an important endemic infectious disease in many pig rearing countries. There is a huge necessity of an effective and economically affordable vaccine for SD, e.g., a single strain based vaccine for CD.